This proposal is submitted in response to RFA HL-02-002. Like murine CMV, y,HV68 causes chronic vasculitis restricted to the great elastic arteries (elastic arteritis). The major findings from years 1-3 of RO1 HL60090 relevant to this proposal were that: (i) persistent viral replication in the smooth muscle cells of the media of the great elastic arteries is responsible for arteritis, (ii) the media of the great elastic arteries is an immunoprivileged site, (iii) the yHV68 v-cyclin and v-bcl-2 are important for induction of arteritis, and iv) IFN,/and likely CD4 T cells protect against virus induced arteritis. To determine whether viral injury triggers atherosclerosis, we performed preliminary studies and discovered that 7HV68 triggers atherosclerosis in apoE-/- mice. In this proposal we test the hypothesis, based on our data and data in the literature, that the viral and immune mechanisms that regulate elastic arteritis are the same as those that regulate virus induced atherosclerosis. The progress made during the first 3 years of R01HL60090, and new preliminary data, will allow us to define mechanisms responsible for induction of and protection against elastic arteritis and the relationship between virus induced arteritis, immunity, and development of atherosclerosis* via the following Aims. Aim 1. Determine the role of T cells in virus induced elastic arteritis Aim 2. Characterize the pathogenesis of virus induced atherosclerosis* in apoE-/- mice Aim 3. Identify the immune mechanisms that protect against or enhance vires induced atherosclerosis* By performing these studies we hope to define immune and viral mechanisms that operate to protect or to damage the great vessels, and to determine the relationship between these mechanisms and the development of atherosclerosis. This will allow us to manipulate the immune system to prevent atherosclerosis induction by virus infection, and potentially to vaccinate against virus induced atherosclerosis.